tbuckley/cabot-search huggingface dataset:
Macromolecular NO‐Donor Micelles for Targeted and Augmented Chemotherapy against Prostate Cancer
Authors: Jiaxin Chen, Bingbing Zhao, Junhui Zou, Jiachen Yang, Lifen Yang, Junmei Zhang, Wei Chen, Dechun Huang, Yinan Zhong
Journal: Advanced Healthcare Materials (2022)

Mitoxantrone (MTO) is clinically utilized for treating hormone-refractory prostate cancer (PCa), however, the therapeutic outcome is far from optimal due to the lack of proper drug carrier as well as the inherent MTO detoxification mechanisms of DNA lesion repair and anti-oxidation. Herein, a bombesin-installed nanoplatform combining the chemotherapeutic MTO and the chemotherapeutic sensitizer of nitric oxide (NO) is developed based on MTO-loaded macromolecular NO-donor-containing polymeric micelles (BN-NMMTO ) for targeted NO-sensitized chemotherapy against PCa. BN-NMMTO actively target and accumulates in PCa sites and are internalized into the tumor cells. The macromolecular NO-donor of BN-NMMTO undergoes a reductive reaction to unleash NO upon intracellular glutathione (GSH), accompanying by micelle swelling and MTO release. The targeted intracellular MTO release induces DNA lesion and reactive oxygen species (ROS) generation in tumor cells without damage to the normal cells, and MTO's cytotoxicity is further augmented by NO release via the inhibition of both DNA repair and anti-oxidation pathways as compared with traditional MTO therapies.
The risk of coronavirus disease 2019 (COVID-19) among individuals with monoclonal B cell lymphocytosis
Authors: Sameer A. Parikh, Sara J. Achenbach, Kari G. Rabe, Aaron D. Norman, Nicholas J. Boddicker, Janet E. Olson, Timothy G. Call, James R. Cerhan, Celine M. Vachon, Neil E. Kay, Esteban Braggio, Curtis A. Hanson, Susan L. Slager, Tait D. Shanafelt
Journal: Blood Cancer Journal (2022)
Bruton tyrosine kinase inhibitors in the management of Waldenström macroglobulinemia
Authors: Jorge J. Castillo, Christian Buske, Judith Trotman, Shayna Sarosiek, Steven P. Treon
Journal: American Journal of Hematology (2022)

Bruton tyrosine kinase (BTK) inhibitors have taken a central role in the management of patients with Waldenström macroglobulinemia and are the only agents approved by the Food and Drug Administration (FDA) to treat these patients. Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations. Herein, we review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors.
Altered Risk of Incident Gout According to Changes in Metabolic Syndrome Status: A Nationwide, <scp>Population‐Based</scp> Cohort Study of 1.29 Million Young Men
Authors: Yeonghee Eun, Kyungdo Han, Seung Woo Lee, Kyunga Kim, Seonyoung Kang, Seulkee Lee, Hoon‐Suk Cha, Eun‐Mi Koh, Hyungjin Kim, Jaejoon Lee
Journal: Arthritis & Rheumatology (2022)

Few data are available on whether changes in metabolic syndrome affect incident gout. This study was undertaken to assess associations between metabolic syndrome status and incident gout, as well as changes in the clinical characteristics of metabolic syndrome and incident gout, in a cohort of young men.This nationwide, population-based cohort study included 20-39-year-old men who participated in serial health check-ups. The outcome, incident gout, was defined according to the claims database diagnostic code for gout. Associations among changes in metabolic syndrome status and incident gout were analyzed using Cox proportional hazards models.Among 1,293,166 individuals, 18,473 were diagnosed as having gout (incidence rate 3.36 per 1,000 person-years). Subjects who had chronic metabolic syndrome (defined as metabolic syndrome at all 3 health check-ups) had a nearly 4-fold higher risk of incident gout compared to subjects who did not have metabolic syndrome at any of the 3 health check-ups (adjusted hazard ratio [HRadj ] 3.82 [95% confidence interval (95% CI) 3.67-3.98]). Development of metabolic syndrome more than doubled the risk of incident gout (HRadj 2.31 [95% CI 2.20-2.43]). Conversely, recovery from metabolic syndrome reduced the risk of incident gout by nearly half (HRadj 0.52 [95% CI 0.49-0.56]). Among metabolic syndrome components, changes in elevated triglycerides (development of elevated triglycerides, HRadj 1.74 [95% CI 1.66-1.81]; recovery from elevated triglycerides, HRadj 0.56 [95% CI 0.54-0.59]) and abdominal obesity (development of abdominal obesity, HRadj 1.94 [95% CI 1.85-2.03]; recovery from abdominal obesity, HRadj 0.69 [95% CI 0.64-0.74]) showed the greatest association with altered risk of incident gout. Associations between changes in the status and clinical characteristics of metabolic syndrome and incident gout were more pronounced in subjects ages 20-29 years compared to those ages 30-39 years, and in subjects who were underweight or who had a normal weight.Changes in the status and clinical characteristics of metabolic syndrome were associated with altered risk of incident gout. These results suggest that metabolic syndrome is a modifiable risk factor for gout.
Within or Without You? A Perspective Comparing In Situ and Ex Situ Tissue Engineering Strategies for Articular Cartilage Repair
Authors: Cathal D. O'Connell, Serena Duchi, Carmine Onofrillo, Lilith M. Caballero‐Aguilar, Anna Trengove, Stephanie E. Doyle, Wiktor J. Zywicki, Elena Pirogova, Claudia Di Bella
Journal: Advanced Healthcare Materials (2022)

Human articular cartilage has a poor ability to self-repair, meaning small injuries often lead to osteoarthritis, a painful and debilitating condition which is a major contributor to the global burden of disease. Existing clinical strategies generally do not regenerate hyaline type cartilage, motivating research toward tissue engineering solutions. Prospective cartilage tissue engineering therapies can be placed into two broad categories: i) Ex situ strategies, where cartilage tissue constructs are engineered in the lab prior to implantation and ii) in situ strategies, where cells and/or a bioscaffold are delivered to the defect site to stimulate chondral repair directly. While commonalities exist between these two approaches, the core point of distinction-whether chondrogenesis primarily occurs "within" or "without" (outside) the body-can dictate many aspects of the treatment. This difference influences decisions around cell selection, the biomaterials formulation and the surgical implantation procedure, the processes of tissue integration and maturation, as well as, the prospects for regulatory clearance and clinical translation. Here, ex situ and in situ cartilage engineering strategies are compared: Highlighting their respective challenges, opportunities, and prospects on their translational pathways toward long term human cartilage repair.
The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression
Authors: Dorothea L. Floris, Han Peng, Varun Warrier, Michael V. Lombardo, Charlotte M. Pretzsch, Clara Moreau, Alex Tsompanidis, Weikang Gong, Maarten Mennes, Alberto Llera, Daan van Rooij, Marianne Oldehinkel, Natalie J. Forde, Tony Charman, Julian Tillmann, Tobias Banaschewski, Carolin Moessnang, Sarah Durston, Rosemary J. Holt, Christine Ecker, Flavio Dell’Acqua, Eva Loth, Thomas Bourgeron, Declan G.M. Murphy, Andre F. Marquand, Meng-Chuan Lai, Jan K. Buitelaar, Simon Baron-Cohen, Christian F. Beckmann
Journal: American Journal of Psychiatry (2022)

The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression.Using a novel deep learning framework trained to predict biological sex based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age).Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types.The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.
SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance
Authors: Hao Xie, Yu-Han Wang, Xin Liu, Jia Gao, Chunliang Yang, Teng Huang, Lu Zhang, Xi Luo, Zhichao Gao, Ting Wang, Tong Yan, Yanjun Liu, Ping Yang, Qilin Yu, Shiwei Liu, Yi Wang, Fei Xiong, Shu Zhang, Qing Zhou, Cong-Yi Wang
Journal: Metabolism (2022)
Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis
Authors: Pierre Nahon, Jessica Bamba-Funck, Richard Layese, Eric Trépo, Jessica Zucman-Rossi, Carole Cagnot, Nathalie Ganne-Carrié, Cendrine Chaffaut, Erwan Guyot, Marianne Ziol, Angela Sutton, Etienne Audureau, Pierre Nahon, Tarik Asselah, Dominique Guyader, Stanislas Pol, Hélène Fontaine, Georges-Philippe Pageaux, Victor De Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean-Pierre Bronowicki, Thomas Decaensi, Ghassan Riachi, Paul Calès, Jean-Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Sebastien Dharancy, Jean-Frédéric Blanc, Armand Abergel, Olivier Chazouillères, Ariane Mallat, Jean-Didier Grangé, Pierre Attali, None Louis d’Alteroche, Claire Wartelle, Thông Dao, Dominique Thabut, Christophe Pilette, Christine Silvain, Christos Christidis, Eric Nguyen-Khac, Brigitte Bernard-Chabert, Sophie Hillaire, Vincent Di Martino, Nathalie Ganne-Carrié, Cendrine Chaffaut, Isabelle Archambeaud, Louis d’Alteroche, Frédéric Oberti, Dominique Roulot, Christophe Moreno, Alexandre Louvet, Thông Dao, Romain Moirand, Odile Goria, Eric Nguyen-Khac, Nicolas Carbonell, Jean-Charles Duclos-Vallée, Stanislas Pol, Victor de Ledinghen, Violaine Ozenne, Jean Henrion, Jean-Marie Péron, Albert Tran, Gabriel Perlemuter, Xavier Amiot, Jean-Pierre Zarski, Sylvie Chevret
Journal: Journal of Hepatology (2022)
P2X1 enhances leukemogenesis through PBX3-BCAT1 pathways
Authors: Xiaoxiao He, Yilu Xu, Dan Huang, Zhuo Yu, Jing Yu, Li Xie, Ligen Liu, Ye Yu, Chiqi Chen, Jiangbo Wan, Yaping Zhang, Junke Zheng
Journal: Leukemia (2022)

Abstract How bone marrow niches regulate leukemogenic activities of leukemia-initiating cells (LICs) is unclear. The present study revealed that the metabolic niche component, ATP, efficiently induced ion influx in LICs through its ligand-gated ion channel, P2X1. P2X1 deletion impaired LIC self-renewal capacities and resulted in an approximately 8-fold decrease in functional LIC numbers in a murine acute myeloid leukemia (AML) model without affecting normal hematopoiesis. P2X1 phosphorylation at specific sites of S387 and T389 was essential for sustaining its promoting effects on leukemia development. ATP-P2X1-mediated signaling upregulated the PBX3 level to transactivate BCAT1 to maintain LIC fates. P2X1 knockdown inhibited the proliferation of both human AML cell lines and primary cells. The P2X1 antagonist sufficiently suppressed AML cell proliferation. These results provided a unique perspective on how metabolic niche factor ATP fine-tunes LIC activities, which may benefit the development of strategies for targeting LICs or other cancer stem cells.
Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer
Authors: Yongxi Liang, Delin Min, Hulin Fan, Kunlin Liu, Juchuanli Tu, Xueyan He, Bingjie Liu, Lu Zhou, Suling Liu, Xun Sun
Journal: Acta Pharmaceutica Sinica B (2022)

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.
Biomimetic Nanovaccines Potentiating Dendritic Cell Internalization via CXCR4‐Mediated Macropinocytosis
Authors: Chao Yang, Fan Zhang, Fangman Chen, Zhimin Chang, Yuewu Zhao, Dan Shao, Wen Sun, Wen‐fei Dong, Zheng Wang
Journal: Advanced Healthcare Materials (2022)

Although targeted delivery of nanoparticulate vaccines to dendritic cells (DCs) holds tremendous potential, it still faces insufficient internalization and endosome degradation via the receptor-mediated endocytosis pathway. Inspired by the advantages of CXC-chemokine receptor type 4 (CXCR4)-mediated macropinocytosis in the internalization of DCs, a multifunctional vaccine is constructed based on a reactive oxygen species (ROS)-responsive nanoparticulate core and macropinocytosis-inducing peptide-fused cancer membrane shell, allowing the direct cytosolic delivery of cancer membrane-associated antigen and a stimulator of interferon genes (STING) agonist, cGAMP for highly efficient cancer immunotherapy. The biomimetic nanovaccines show a dramatically enhanced cellular uptake by DCs via CXCR4-mediated macropinocytosis. Such a direct delivery process promotes cytosolic release of cGAMP in response to ROS, and together promoted DC maturation and T cell priming by activating the STING pathway. Consequently, the biomimetic nanovaccines not only result in a great tumor rejection in prophylactic B16-F10 melanoma murine model, but also markedly suppress the growth of established melanoma tumors when combined with anti-PD-1 checkpoint blockade. This study advances the design of biomimetic nanovaccines and provides a promising strategy for macropinocytosis-mediated cancer vaccination.
Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling
Authors: Alberto Canfrán-Duque, Noemi Rotllan, Xinbo Zhang, Irene Andrés-Blasco, Bonne M. Thompson, Jonathan Sun, Nathan L. Price, Marta Fernández-Fuertes, Joseph W. Fowler, Diego Gómez-Coronado, William C. Sessa, Chiara Giannarelli, Robert J. Schneider, George Tellides, Jeffrey G. McDonald, Carlos Fernández-Hernando, Yajaira Suárez
Journal: Circulation (2022)

Background: Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear. Methods: The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of CH25H in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or Ch25h –/– mice to lethally irradiated Ldlr –/– mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from Ldlr –/– or Ch25h–/–;Ldlr–/– mice . The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage–tracing mouse model, Myh11 ERT2CRE mT/mG;Ldlr –/– , adoptively transferred with wild-type or Ch25h –/– mice bone marrow followed by 12 weeks of Western diet feeding. Results: We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB–mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC–mediated modulation of liver X receptor or SREBP (sterol regulatory element–binding protein) transcriptional activity. Conclusions: Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.
Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children
Authors: Brittany P. Boribong, Thomas J. LaSalle, Yannic C. Bartsch, Felix Ellett, Maggie E. Loiselle, Jameson P. Davis, Anna L.K. Gonye, David B. Sykes, Soroush Hajizadeh, Johannes Kreuzer, Shiv Pillai, Wilhelm Haas, Andrea G. Edlow, Alessio Fasano, Galit Alter, Daniel Irimia, Moshe Sade-Feldman, Lael M. Yonker
Journal: Cell Reports Medicine (2022)

Multisystem inflammatory syndrome in children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism that is distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature.
PROTAC therapy as a new targeted therapy for lung cancer
Authors: Jennifer W. Li, Guangrong Zheng, Frederic J. Kaye, Lizi Wu
Journal: Molecular Therapy (2022)

Despite recent advances in molecular therapeutics, lung cancer is still a leading cause of cancer deaths. Currently, limited targeted therapy options and acquired drug resistance present significant barriers in the treatment of patients with lung cancer. New strategies in drug development, including those that take advantage of the intracellular ubiquitin-proteasome system to induce targeted protein degradation, have the potential to advance the field of personalized medicine for patients with lung cancer. Specifically, small molecule proteolysis targeting chimeras (PROTACs), consisting of two ligands connected by a linker that bind to a target protein and an E3 ubiquitin ligase, have been developed against many cancer targets, providing promising opportunities for advanced lung cancer. In this review, we focus on the rationale for PROTAC therapy as a new targeted therapy and the current status of PROTAC development in lung cancer. Despite recent advances in molecular therapeutics, lung cancer is still a leading cause of cancer deaths. Currently, limited targeted therapy options and acquired drug resistance present significant barriers in the treatment of patients with lung cancer. New strategies in drug development, including those that take advantage of the intracellular ubiquitin-proteasome system to induce targeted protein degradation, have the potential to advance the field of personalized medicine for patients with lung cancer. Specifically, small molecule proteolysis targeting chimeras (PROTACs), consisting of two ligands connected by a linker that bind to a target protein and an E3 ubiquitin ligase, have been developed against many cancer targets, providing promising opportunities for advanced lung cancer. In this review, we focus on the rationale for PROTAC therapy as a new targeted therapy and the current status of PROTAC development in lung cancer.
Is cognitive behavioral therapy for insomnia (CBTi) efficacious for treating insomnia symptoms in shift workers? A systematic review and meta-analysis
Authors: Amy C Reynolds, Alexander Sweetman, Meagan E Crowther, Jessica L Paterson, Hannah Scott, Bastien Lechat, Sian E Wanstall, Brandon Wj Brown, Nicole Lovato, Robert J Adams, Peter R Eastwood
Journal: Sleep Medicine Reviews (2022)
Small extracellular vesicle targeting of hypothalamic AMPKα1 promotes weight loss in leptin receptor deficient mice
Authors: Edward Milbank, Nathalia Dragano, Xavi Vidal-Gómez, Verónica Rivas-Limeres, Pablo Garrido-Gil, Mireille Wertheimer, Sylvain Recoquillon, María P. Pata, José Luis Labandeira-Garcia, Carlos Diéguez, Rubén Nogueiras, M. Carmen Martínez, Ramaroson Andriantsitohaina, Miguel López
Journal: Metabolism (2022)
Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy
Authors: Masato Akiyama, Masahiro Miyake, Yukihide Momozawa, Satoshi Arakawa, Maiko Maruyama-Inoue, Mikiko Endo, Yusuke Iwasaki, Kazuyoshi Ishigaki, Nana Matoba, Yukinori Okada, Miho Yasuda, Yuji Oshima, Shigeo Yoshida, Shin-ya Nakao, Kazuya Morino, Yuki Mori, Ai Kido, Aki Kato, Tsutomu Yasukawa, Ryo Obata, Yoshimi Nagai, Kanji Takahashi, Kimihiko Fujisawa, Akiko Miki, Makoto Nakamura, Shigeru Honda, Hiroaki Ushida, Tetsuhiro Yasuma, Koji M. Nishiguchi, Ryusaburo Mori, Koji Tanaka, Yu Wakatsuki, Kenji Yamashiro, Kazuaki Kadonosono, Chikashi Terao, Tatsuro Ishibashi, Akitaka Tsujikawa, Koh-Hei Sonoda, Michiaki Kubo, Yoichiro Kamatani
Journal: Ophthalmology (2022)